Identification of a novel nonsense ATP2A2 gene variant in a patient with Darier’s disease flare following COVID-19 infection: A case report

Rationale: Darier disease (DD) is a rare autosomal dominant disorder that primarily manifests as hyperkeratotic papules and itching. The underlying etiology of DD is pathogenic variation in the ATP2A2 gene. However, this disease has a high penetrance but variable expressivity, indicating that patients inheriting the genotype may have different manifestations due to exogenous factors. Meanwhile, a few reports have documented that COVID-19 may be implicated in the flare of DD. Patient concerns: A 51-year-old man presented with keratotic papules and scaly erythematous rash on his trunk with pruritus after being infected with COVID-19. Laboratory test results were normal. Histological analysis revealed epidermal hyperkeratosis and intraepidermal lacunae containing dyskeratinized cells. Genetic analysis revealed a novel variant of ATP2A2 (c.815G>A, p.Trp272*), which was considered pathogenic in this case. Diagnoses: The patient was diagnosed as having DD. Interventions: Oral acitretin and topical corticosteroid hormone ointments were used. Outcomes: The patient achieved complete resolution of symptoms during the 3-month follow-up period. Lessons: We revealed the first novel ATP2A2 variant (c.815G>A, p.Trp272*) in the flare of DD following COVID-19 infection. Additionally, this pathogenic variant enriches the ATP2A2 gene mutation spectrum.


Introduction
Darier disease (DD; OMIM #124200) is a rare autosomal dominant genodermatosis.The prevalence of DD is estimated to be approximately 1 in 30,000 to 100,000 individuals worldwide, affecting all ethnic groups and sexes equally. [1]Clinically, DD commonly presents as keratotic papules accompanied by itching and malodor, primarily affecting seborrheic areas of the body. [2]istopathological analysis revealed acantholysis and dyskeratosis, hallmarks of this disorder. [3]Previous studies have identified pathogenic mutations in ATP2A2 as the underlying cause of DD. [4] However, there are still gaps in our understanding of this condition, particularly regarding specific genetic variants and their association with disease severity and progression.
Recent studies have shed light on the dermatological manifestations of COVID-19.These skin manifestations in COVID-19 patients range from mild to severe and include urticarial rash, morbilliform rash, papulovesicular exanthem, and livedo reticularis. [5]Notably, emerging reports have suggested a potential association between COVID-19 and flare-ups of preexisting DD. [6] Therefore, it is crucial to understand the interplay between COVID-19 and DD.Exploring the relationship between these 2 conditions may provide valuable insights into the pathophysiology of DD and the effect of viral infections on disease.
Given the ongoing COVID-19 pandemic, it is crucial to recognize the potential impact of viral infections on dermatological disorders and their clinical outcomes.This study presents the case of a patient with DD flare following COVID-19 infection.The focus of this study was to detect novel genetic variants that contribute to the pathogenesis of the patient and investigate their association with disease flare following COVID-19 infection.

The present study was supported by the Sichuan Medical Youth Innovation Research Project (Q23014).
We confirmed that the patient involved in the case report gave his consent for images and medical data to be published, and written informed consent for publication was obtained.

Case report
A 51-year-old Chinese male presented with a 4-month history of keratotic papules and a scaly erythematous rash on his trunk accompanied by pruritus.Prior to the onset of these symptoms, the patient had experienced a COVID-19 infection characterized by flu-like symptoms, including fever.Within a few days of the fever subsiding, a rash appeared on the trunk.The patient had a history of eczema, but had never encountered such severe symptoms in the past.He denied experiencing chills, cough, sore throat, diarrhea, or joint pain, and no similar rashes were reported by any household member.
Physical examination revealed extensive keratotic papules and a scaly erythematous rash on the patient's trunk (Fig. 1).The laboratory examination results were unremarkable.Histological analysis revealed epidermal hyperkeratosis and intraepidermal lacunae containing dyskeratinized cells (Fig. 2).
Next-generation sequencing identified a heterozygous variant (c.815G>A, p.Trp272*) in ATP2A2.This variant led to the substitution of tryptophan with a stop codon (p.Trp272*) (Fig. 3), resulting in functional changes in the protein.Importantly, this variant was absent from the patient's family members and in a cohort of 100 unrelated controls.Its novelty was confirmed as it had not been documented in the ExAC, ESP, 1000G, or HGMD databases.According to the guidelines of the American College of Medical Genetics and Genomics (PSV1 + PM2 + PP2), this novel variant was classified as pathogenic. [7]Based on these findings, the patient was diagnosed with DD and was subsequently treated with oral acitretin and topical corticosteroid hormone ointment for an appropriate duration.The patient achieved complete resolution of symptoms during the 3-month follow-up period.
This study was approved by the Ethics Committee of Suining Central Hospital and adhered to the tenets of the Declaration of Helsinki.

Discussion
This study describes a clinically diagnosed patient with DD harboring a novel heterozygous variant of ATP2A2.Clinically, DD manifests as hyperkeratotic papules primarily affecting the seborrheic area, which often should be distinguished from seborrheic dermatitis, acanthosis nigricans, Grover disease, and Hailey-Hailey disease. [8]In this patient, dyskeratosis and acantholysis, which characterize DD, were observed on histopathology.The clinical manifestations and histopathology of the patient were consistent with the diagnosis of DD. [9] Variants in ATP2A2 have been identified as the underlying cause of DD. [10] ATP2A2 encodes sarco/endoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2), which plays a crucial role in maintaining calcium homeostasis within cells. [11]ATP2A2 pathogenic variants result in the production of dysfunctional SERCA2 protein, resulting in decreased ER Ca(2+) concentration in Darier keratinocytes, thus leading to impaired calcium transport and subsequent disruption of cell adhesion and differentiation. [11]The specific genetic ATP2A2 variant (c.815G>A, p.Trp272*) detected in this patient represents a novel nonsense mutation that alters protein function by substituting tryptophan with a stop codon at amino acid position 272 (p.Trp272*).This variant was considered pathogenic based on American College of Medical Genetics and Genomics guidelines. [7]Presumably, this novel nonsense variant results in impaired SERCA2 function leading to aberrant junctional protein processing and impaired keratinocyte cohesion.This impairment potentially causes acantholysis or loss of connection between keratinocytes, as seen on pathology, which predominantly causes clinical manifestations in this case.Previous studies have suggested that nonsense mutations in ATP2A2 are more common in DD patients.Ruiz-Perez reported that the majority (23/40) of mutations in ATP2A2 are likely to result in nonsense-mediated RNA decay. [12]Additionally, over 50% of the mutations lead to a premature termination codon, leading the authors to propose that haploinsufficiency is a common molecular mechanism for DD. [4]ur investigation further supports this hypothesis.However, no genotype-phenotype relationship has been recognized for ATP2A2 in DD, [13] indicating high penetrance but variable expressivity.A possible reason could be that most SERCA2 protein functions were affected independently of the type or location of ATP2A2 variants, [13] and the phenotypic variability could also be due to additional environmental factors. [14]D is primarily triggered by exogenous factors, such as sun exposure, friction, or infection. [15]The potential association between COVID-19 and flare-ups in DD is an intriguing area of research, as viral infections are known to trigger exacerbations in various dermatological conditions including DD. [16] Some reports have suggested that SARS-CoV-2 may act as an environmental trigger for DD. [17]The immune dysregulation and systemic inflammation induced by SARS-CoV-2 infection, including the cytokine storm-like response with tumor necrosis factor-alpha and interleukin-6, may downregulate ATP2A2 mRNA levels.These pro-inflammatory cytokines and cellular immune responses can further disrupt calcium homeostasis, exacerbating the underlying pathophysiological mechanisms of DD through acantholysis and apoptosis. [18]owever, further research is needed to fully understand the precise mechanisms by which COVID-19 affects the course of DD.
The identification of the novel nonsense ATP2A2 gene variant in this patient with COVID-19 provides valuable insights into the pathogenesis of DD associated with viral infections.The interaction between this genetic variant and inflammation and immune dysregulation induced by COVID-19 may have contributed to the observed disease flare-up in this patient.Understanding these mechanisms could lead to targeted therapeutic interventions and personalized management strategies for DD patients.

Conclusion
In conclusion, our study identified a novel nonsense ATP2A2 variant in a patient with DD who experienced a disease flare  following COVID-19 infection.This finding the gene spectrum associated with DD and highlights the potential influence of COVID-19 on disease flares.The precise mechanisms underlying the interaction between DD and COVID-19 require further investigation to better understand the pathophysiology and develop targeted interventions for patients with this condition.

Figure 1 .
Figure 1.Photo of the patient demonstrating extensive keratotic papules and scaly erythematous rash on the patient's trunk regions.